Santana tied a team record for homers in a series, finishing off this four-game set with a pair of two-run shots. He has homered in three straight games, and has hit six home runs in six games.
"I know I'm hot, but I'm taking the same approach," Santana said. "This can happen in this game when a player gets focused. It's a help to the team."
Santana and the Indians ended a four-game losing skid and stopped the Royals' five-game winning streak.
Santana went 3 for 3 and reached base in all five plate appearances, including drawing his major league-leading 72nd walk. The switch-hitter homered in a four-run fifth inning and hit another drive in the ninth for his fifth career multihomer game and his second of the series.
"It was pretty impressive to watch," teammate Mike Aviles said. "Everybody knows how big he can be. He was able to drive some balls out of the park consistently from both sides."
"Watching him all season, he has an unbelievable eye. I know his average isn't where he wants it to be, but he got off to a slow start. But even through his struggles early in the year, he was able to find ways to get on base. You knew with a guy like him it was only a matter of time before he got back on pace."
In his past six games, Santana is 14 for 23, including three doubles and 10 RBIs.
"He's hot as a firecracker," Royals manager Ned Yost said. "He's hitting home runs right-handed. He's hitting home runs left-handed."
Danny Salazar (3-4) gave up three runs and seven hits over seven innings. He walked none and struck out seven.
Bruce Chen (2-3) allowed up six runs and eight hits in five-plus innings.
Nick Swisher hit an RBI single in the Indians seventh to end an 0-for-21 streak.
Billy Butler had three hits for the Royals, including an RBI double. He had homered in his previous two games, but Santana equaled Butler's season home run total in the series.
"Santana has got a lot of pop," Butler said. "He's in one of those zones. A lot of guys get hot, but don't hit four homers in a series. Five, sorry, I missed one. It just shows you how impressive it is. He's very talented, a very strong guy."
Santana is the first player to hit five home runs in a series since Hunter Pence for San Francisco against the Dodgers last September.
Santana tied an Indians record for most home runs in a series. The others were Hal Trosky (1934), Joe Carter (1989), Albert Belle (1995), Matt Williams (1997) and Travis Hafner (2004). Hafner did it in two-game series against the Angels.
After missing five games with back problems, SS Asdrubal Cabrera started for the Indians. 3B Lonnie Chisenhall was held out the second straight game with a stomach virus. ... Royals RHP Wade Davis has not allowed an extra-base hit this season in 44 2/3 innings. ... The Indians will activate RHP Justin Masterson on Friday and start him against Texas. Masterson, a 14-game winner last year, is on the disabled list with right knee inflammation. ... Chen picked Aviles off first to end the third inning. It was Chen's 45th career pickoff, which ranks fourth among active pitchers. ... Three of Raburn's seven hits against Chen are home runs.